1. Field of the Invention
The present invention relates to a simplified process for preparing a product of carbapenem antibiotic compounds.
2. The Prior Arts
Carbapenem is a class of β-lactam antibiotics having a broader spectrum of antibacterial activity than other β-lactam antibiotics. The formula (I) has an unusual structure of carbapenem, which renders itself strongly resistant to typical bacterial beta-lactamse enzymes. In other words, carbapenem is able to be used as the last resort for many serious bacterial infections including gram positive and negative, aerobic and anaerobic bacteria. However, unstable propriety of carbapenem brings about a problem in commercially manufacturing. As the environmental temperature goes up, accelerating dimerization and hydrolysis deteriorate the quality of carbapenem. Take ertapenem for example, it is unstable above −20° C. and must be stored at a low temperature. Therefore, several researches disclose how to achieve a stable form of carbapenem antibiotics in its formulation and manufacturing process. In particular, several processes for conversion of salt-containing carbapenem to a formulation of the compound of formula (II) have been reported.

WO2001/32172 A1 describes a process with detail steps for converting ertapenem monosodium into a stable formulation. The whole process contains more than 10 steps. Even though WO2002/34750 A1 describes a similar formulation process for carbapenem antibiotics comprising the following steps of: (1) charging a solution of carbon dioxide source having a pH range of about 6.0˜12.0; (2) adding an effective amount of a mole ratio of a base and active ingredient into the reaction vessel containing the solution of carbon dioxide source to maintain pH at about 6.0 to 9.0 and a temperature of about −3° C. to about 15° C.; (3) lyophilizing the solution of step (2) to yield the final formulation product of a compound of formula (I) with less than about 10% of moisture content. The actual manufacturing process of the later patent still follows more than 10 steps, including charging water for injection 3 times, weighting, carefully maintaining a pH range by alternately adding carbapenem and base.
With our continued research for developing different processes for converting carbapenem or its pharmaceutically acceptable salt, hydrate, or solvate to a final formulation product of carbapenem antibiotic with acceptable levels of degradates, solid state stability and solution stability for dosing. The process mainly simplifies the manufacturing process avoiding multiple water charging and titration, and also offers a high-quality and ready-to-use injection suitable for treatment. The other process is a crystallization directly using anti-solvent to obtain the final formulation product without lyophilizing. The present invention is able to offer a commercially viable, very low-cost, and simplified the manufacturing processes.